Abstract
To identify putative gene regulatory regions that respond to epidermal injury, we mapped chromatin dynamics in a stratified human epidermis during barrier maturation and disruption. Engineered skin substitutes (ESS) cultured at the air-liquid interface were used as a model of developing human epidermis with incomplete barrier formation. The epidermal barrier stabilized following engraftment onto immunocompromised mice, and was compromised again upon injury. Modified formaldehyde-assisted isolation of regulatory elements (FAIRE) was used to identify accessible genomic regions characteristic of monolayer keratinocytes, ESS in vitro, grafted ESS, and tape-stripped ESS graft. We mapped differentiation- and maturation-associated changes in transcription factor binding sites enriched at each stage and observed overrepresentation of AP-1 gene family motifs in barrier-deficient samples. Transcription of TSLP, an important effector of immunological memory in response to allergen exposure, was dramatically elevated in our barrier-deficient samples. We identified dynamic DNA elements that correlated with TSLP induction and may contain enhancers that regulate TSLP. Two dynamic regions were located near the TSLP promoter and overlapped with allergy-associated SNPs rs17551370 and rs2289877, strongly implicating these loci in the regulation of TSLP expression in allergic disease. Additional dynamic chromatin regions ~250kb upstream of the TSLP promoter were found to be in high linkage disequilibrium with allergic disease SNPs. Taken together, these results define dynamic chromatin accessibility changes during epidermal development and dysfunction.
Highlights
A major role of the epidermis is to act as a barrier that protects against external pathogens and prevents surface water loss
Engineered skin substitutes (ESS) grafts provide an adequate model of human epidermis and enable the study of thymic stromal lymphopoietin (TSLP) regulation during ESS maturation and as triggered by human epidermal barrier disruption
To further delineate which peaks may be associated with allergic or atopic disease, we investigated the association between dynamic formaldehyde-assisted isolation of regulatory elements (FAIRE) peaks and specific single nucleotide polymorphisms (SNPs)
Summary
A major role of the epidermis is to act as a barrier that protects against external pathogens and prevents surface water loss. Disruption of the barrier induces an immune response to destroy. Chromatin dynamics in human epidermal barrier invading organisms and create immunological memory against specific antigens. Dysregulation of this process can involve ectopic activation of the Th2 immune system and lead to allergic diseases including atopic dermatitis, asthma, and allergic rhinitis. Downstream of barrier disruption are a series of cellular responses, including changes in gene expression. Analysis of chromatin accessibility dynamics can identify potential regulatory regions that mediate the transcriptional response and provide insight into the mechanisms that link barrier dysfunction with immune sensitization
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